1-aminoalkyl-amino-indanes and salts thereof



United States Patent 3,408,389 l-AMINOALKYL-AMINO-INDANES AND SALTSTHEREOF Jack Bernstein, New Brunswick, and Ervin R. Spitzmiller,

Highland Park, N.J., and Herman A. Bruson, Woodbridge, Conn., assignors,by mesue assignments, to E. R. Squibb & Sons, Inc., New York, N.Y., acorporation of Delaware No Drawing. Filed July 27, 1964, Ser. No.385,458 Claims. (Cl. 260501.2)

This invention relates to new chemical compounds, and more particularly,to compounds of the Formula 1:

and pharmaceutically acceptable acid-addition and quaternary ammoniumsalts thereof, wherein R is hydrogen, lower alkyl (e.g., methyl, ethyland isopropyl), halogen (e.g., bromine, chlorine and fluorine),halomethyl (e.g., trifluoromethyl), lower alkoxy (e.g., methoxy, ethoxy,propoxy and amyloxy), aryloxy (e.g., phenoxy), or di- (loweralkyl)an1ino (e.g., dimethylamino and diethylamino); R' and R" eachrepresents lower alkyl (e.g., methyl, ethyl and isopropyl); monocyclicaryl (e.g., phenyl and o, m, and p-tolyl); halophenyl; halomethylphenyl(e.g., m-trifluoromethylphenyl); lower alkoxyphenyl (e.g.,m-methoxyphenyl); monocyclic aryl (lower alkyl) (e.g., benzyl,phenethyl, and ,B-phenylpropyl); and halo, halomethyl, and lower alkoxysubstituted monocyclic aryl (lower alkyl) and B is a basic,nitrogen-containing radical such as amino, (lower alkyl) amino, di(loweralkyl)amino (e.g., dimethylamino and diethyla'mino), hydroxy(loweralkyl) amino, di[hydroxy(lower alkyl)]- amino, halo(lower alkyl)amino,di[hydroxy(lower alkyl)]amino, (lower alkyl)ara1kylamino, aralkylamino(e.g., benzylamino), piperidyl (e.g., piperidino), (lower alkyl)piperidyl (e.g., 2, 3 and 4-methylpiperidino), di- (lower alkyl)piperidyl (e.g., 2,4-, 2,6- and 3,5-dimethylpiperidino); homopiperidyl;pyrrolidyl (e.g., pyrrolidino), (lower alkyl)pyrrolidyl, di(loweralkyl)-pyrrolidyl, piperazinyl (e.g., piperazino), homopiperazinyl,(lower alkyl) piperazinyl (e.g., N -methylpiperazino), di(loweralkyl)piperazinyl, (lower alkoxy) piperazinyl, arylpiperazinyl (e.g.,R-substituted phenylpiperazino, such as 4- phenylpiperazino),aralkylpiperazinyl (e.g., R-substituted phenyl(lower alkyl) -piperazino)such as benzylpiperazino and p chlorophenetbyl piperazino,pyridylpiperazinyl [e.g., 4-(3-pyridyl)piperazino], pyridyl(loweralkyl)piperazinyl [e.g., 4-(3-pyridylmethyl)-piperazino],(alkanoyl-lower alkyl)piperazinyl [e.g., 4-(2-acetoxyethyl) piperazino],(hydroxy-lower alkyl)piperazinyl [e.g., 4-(2- hydroxyethy1)piperazino],homopiperazinyl, morpholinyl (e.g., morpholino), (loweralkyl)morpholinyl, di(lower alkyl)morpholinyl, thiarnorpholinyl (e.g.,thiamorpholino), (lower alkyl)thiamorpholinyl and di(lo'wer alkyl)-thiamorpholinyl. The terms lower alkyl, lower alkoxy, and lower alkyleneas employed herein, include both straight and branched chain radicals ofless than eight carbon atoms.

The preferred compounds of this invention are those of Formula I inwhich R is hydrogen, R is methyl and R" is methyl or phenyl, loweralkylene is ethylene or isopropylene, and B is dimethylamino orN-methyl-N-phenethylamino.

NH- (lower alkylene) B Patented Oct. 29, 1968 Examples of suitableacid-addition salts of the free bases of this invention include themineral acid salts, such as the hydrohalides e.g. hydrochloride,hydrobromide and hydroiodide), the sulfate and the phosphate; andorganic acid salts, such as the citrate, tartrate, oxalate, ascorbate,acetate and succinate. Pharmacologically acceptable acids are, ofcourse, employed where the salt form is prepared for therapeutic use.

Examples of suitable quaternary ammonium salts of the free bases of thisinvention include the lower alkyl halides (e.g., methyl chloride andmethyl bromide), the lower alkyl sulfates (e.g., methosulfate), thearalkyl halides (e.g., benzyl chloride) and the aralkyl sulfates.

The compounds of this invention are physiologically active substanceshaving analgetic activity. The compounds of this invention can beadministered perorally to produce analgesia in the usual perorallyacceptable forms, such as tablets and capsules, the dosage for suchtreatment being adjusted for the activity of the particular compoundemployed.

The compounds of this invention are prepared by the process of thisinvention which comprises reacting a compound of the Formula 11:

-{lowest alkylene)-B EXAMPLE 1 .--N,N-DIMETHYL-N'- (CIS-Z-METHYL- TRANS2 PHENYLINDAN l YL) ETHYL- ENEDIAMINE DIHYDROCHLORIDE A solution of 10g. (0.032 mole) of Z-(dimethylamino) N (2 methyl 2 phenylindan lyl)acetamide in 200 ml. anhydrous ether is added to a suspension of 3 g.(0.076 mole) of lithium aluminum hydride in 300 ml. of ether. Followingthe addition (30 minutes), the reaction mixture is warmed with stirringat reflux temperature for 12 hours. After cooling 9 ml. of water isadded followed by a solution of 2 g. of sodium hydroxide in 10 ml. ofwater. The ethereal solution is decanted and the solid residue is washedwith ether. After drying over magnesium sulfate and filtration the basicethereal solution is cooled in an ice-water bath and 16 ml. of 4 Nalcoholic hydrogen chloride (0.064 mole) is added. The gum whichseparates from solution readily crystallizes and is collected by suctionfiltration. The solid, about 10 g. is recrystallized from ethanol-etherfollowed by recrystallization from methyl ethyl ketone with a recovcryof about 5 g. of product (42%), MP. about 205- 207".

Analysis.Calcd. for C H N -ZHCI: N, 7.62; Cl, 19.39. Found: N, 7.77; CI,19.66.

Similarly, by substituting the following 2-(dimethylamino) N (2,2 R,R"substituted indan-l-yl)acetamides for the2-(dimethylamino)-N(2-methyl-2-phenylindan-l-yl)acetamide in theprocedure of Example 1, the

'3 indicated N,N-dimethyl-N- (2,2-R',R"-substituted-indan-I-yDethyIenediamine dihydrochloride is formed:

4 plien ylindan-l-yl) acetamide' hydrochloride for the amtamide used inthe example, N,2-(cis- 2 -methyl-trans-2- Produet Formed a Reactant R isv R is R is R" 13 2 Methyl-... Methyl Methyl.... Methyl. 3-- --do Eth..do Ethyl. 4.. Phenyl..- p-Tolyl Phenyl--. p Tolyl. 5-- MethyL.-.o-Chlorophenyl-.. Methyl-..- o-Oh 1orophenyl. 6.. -...dop-Trifluoromethylphenyl. -...do p-Trifluoromethylplienyl. 7.. Ethyl....-m-Mothoxyphenyl Etl1yl..... m-Methoxyphenyl. 8 Methyl.... rn-BromophenylMethyl...- m-Bromopheuyl. 9 ..do Benzyl ..do Benzyl. 1O EthylB-Phenet-hyl Ethyl.-..- B-Phenethyl.

EXAMPLE 1l.-N,N-DIMETHY L N (CIS-Z-METH- YL TRANS 2 PHENYL 5CHLOROINDAN- 1 YL)ETHYLENEDIAMINE DIHYDROCHLO- RIDE Following theprocedure of Example 1, but substituting 2 (dimethylamino) N (2methyl-Z-phenyl-5-chloroindan-l-yD-acetamide for the Z-(dimethylamino)-N-(2- phenylindan 1 ylamino)ethyl N methylpiperazine dihydrochloride isobtained.

Similarly by substituting the following 2 B N (2-methyl-Z-phenylindan-l-yl)acetamides for the acetamide in the procedureof Example 1, the indicated N-2-(cis-2- methyltrans-Z-pheriylindan-l-ylamino)ethyl-B dihydrodihydrochloride isobtained..

Reactant B is Example Product formed B is- 21 Methylamino N-methylamine.22. Diethylarm'no N ,N-diethylamine. 23. Benzylamino Nbeuzylamine. 24.Piperidiue. 25. Pyrrolidine. 26. Homopiperidino. Homopiperidine. 27.N-pheuylpiperazino N-phenylpiperazine. 28. N- (2-hydroxyethyl)piperazino- N- 2-hydroxyethyl) piperazLue. 29 HomopiperazinoHomopiperazine. 30 Morp o' o Morpholine. 31 ThiamorpholinoThiamorpholine. 32 Methylphenethylaruino N-methylphenethylamine.

methyI-Z-phenylindan-1-yl)-acetamide, N,N-dimethyl-N'-(cis-Z-methyl-trans-2-pheny1 5 chloroindan-1-yl)ethyl enediaminedihydrochloride is formed.

Similarly, by substituting the following Z-(dimethylamino)-N-(2-methyl 2phenyl R substituted-indan-ly1)acetamides for theZ-(dimethylamino)-N-(2-methyl-2- phenylindan-l-yl)acetamide in theprocedure of Example 1, the indicatedN,N-dimethyl-N'-(cis-2-methyl-trans-2- phenyl R substituted indan 1yl)ethylenediamine hydrochloride is formed:

Example Reactant R is Product Formed 12 4'methyl 4-rnethyl. 13ti'lsopropyl. 14... 5-trifluoromethyl.... 5-tnfluoromethyl. 15.7-methoxy. 16- 4-chloro.

fi-bromo. 18 5-dimethylamino.-.. 5-dimethylammo EXAMPLE 19.-2,N,NTRIMETHYL N (CIS-2- METHYL TRANS 2 PHENYLINDAN 1 YL) ETHYLENEDIAMINEDIHYDROCHLORIDE Following the procedure of Example 1, but substituting 2(N methylpiperazino) N (cis 2 methyl-trans-Z- EXAMPLE 33.N,N DIMETHYL N(CIS 2 METHYL TRANS 2 PHENYLINDAN 1 YT.)- ETHYLENEDIAMINE METHOCHLORIDEA solution of 150.0 g. of material from Example 1 in m1. of acetonitrileis cooled and treated with 25 g. of methyl chloride. After standing forseveral days at room temperature, the solution is diluted to 300 ml.with ether to give the methochloride;

The invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A compound selected from the group consisting of N 11- (lower alkylene) B and the pharmaceutically acceptable acid-addition andquaternary ammonium salts thereof, wherein R is selected from the groupconsisting of hydrogen, lower alkyl, bromine, chlorine, fluorine,trifluoromethyl, lower alkoxy, phenyloxy and di(lower lalkyl)-amino; Rand R" each is selected from the group consisting of lower alkyl,monocyclic aryl, chlorophenyl, bromophenyl, trifiuoromethylphenyl, loweralkoxyphenyl, monocyclic aryl(lower alkyl), and lower alkoxy substitutedmonocyclic aryl (lower alkyl); and B is selected from the groupconsisting of amino, (lower alkyl)amino, di(lower alkyl) amino,hydroxy(lower alkyl)amino, di[hydroxy(lower alkyl)]amino, (loweralkyl)aralkylamino of from 6 to References Cited 12 carbon atoms andaralkylamino of from 6 to 12 carbon UNITED STATES PATENTS atoms.

2. N,N di(lower alkyl) N 2 methyl-Z-phenyl- 2,670,371 2/1954 Cuslc indanl yn (lower a1ky1ene)diamine 5 2,916,490 12/1959 Schenck ct al. 260-5705XR 3. A pharmaceutically acceptable salt of the compound FOREIGN PATENTSof claim 2.

4. N,N dimethyl N (cis-Z-methyl-trans-Z-phenyl- 955497 1/1957 Germanymdan'l'yn'ethylenedlamme' CHARLES B. PARKER, Primary Examiner.

5. A pharmaceutically acceptable salt of the compound of claim 4. 10ROBERT v. HINES, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF